Boron neutron capture therapy (BNCT) is a binary approach to cancer therapy based on the capture of low-energy neutrons by .sup.10 B, which results in the emission of the cytotoxic .sup.7 Li.sup.+ nuclei and .alpha.-particles (.sup.10 B(n,.alpha.).sup.7 Li.sup.+). Tumor-directed antibodies or their immunoreactive fragments are attractive candidates for the selective delivery of .sup.10 B for BNCT, provided that about 1000 .sup.10 B atoms can be attached to each immunoreactive protein without significantly altering its biological properties. A number of attempts have been made to link quantities of boron with tumor-directed antibodies, but these have not been successful in delivering therapeutic quantities of .sup.10 B to tumor cells. One such attempt proceeded by randomly conjugating whole monoclonal antibodies (Mabs) with large numbers of small boron-containing compounds. other attempts have been directed to attaching limited numbers of heterogeneous or homogeneous boron-rich polymers. Variability in these studies has limited the progress realized using these techniques.
These studies have also produced disappointing results. For example, an article by Barth, et al., entitled "Conjugation, Purification, and Characterization of Boronated Monoclonal Antibodies for use in Neutron Capture Therapy," describes a delivery system based on attaching a large number of small boron-containing molecules to an antibody. This study indicated that the boronated antibody had a lower level of specificity for tumor tissue than that typical for a native antibody. Studies, using boronated carboranyl peptides, such as that described by Paxton, et al. in an article entitled "Carboranyl Peptide-Antibody Conjugates for Neutron-Capture Therapy: Preparation, Characterization, and in Vivo Evaluation," have also shown a reduced specificity for boronated antibodies.
An article by Varadarajan, et al., entitled "Novel Carboranyl Amino Acids and Peptides: Reagents for Antibody Modification and Subsequent Neutron-Capture Studies," investigated the use of caged boron molecules coupled to peptides. This technique proved unsatisfactory because of excessive hydrophobic bonding between the peptide and the antibody delivery system.
In addition to the poor results obtained using these techniques, these synthesis techniques are frequently slow, sometimes taking weeks to produce a single delivery system. Moreover, if there is to be an eventual commercialization of this technology, a more manufacturable and predictable process must be developed. Little work has been reported on the use of carboranyl derivatives in oligophosphates. One reported use of a carboranyl derivative is in U.S. Pat. No. 4,399,817 to Benedict entitled "Boron Containing Polyphosphonates for the Treatment of Cancer Tumors." The Benedict reference describes the use of boronated polyphosphonates to delivery boron to calcified tumors. Some of the compounds described incorporate carboranyl derivatives, but these compounds only incorporate carboranyl as an end group and not as a monomer within a oligophosphate.
It is therefore an object of the present invention to produce an phosphate-based boron-rich oligomer that is substantially hydrophilic. It is a further object of this invention to develop a synthesis process which utilizes the substantial technical sophistication of standard DNA synthesis techniques.